1. List factors not in the TNM system that increase the risk for death in patients with thyroid cancer.

2. State the American Thyroid Association (ATA) guidelines for management of thyroid lesions classified as indeterminate on fine needle aspiration (FNA) biopsy and for surgery of differentiated thyroid carcinoma.

3. Discuss the use of FNA for evaluation of thyroid nodules.

4. Describe a technique for performance of FNA that is derived from a consensus of experts in the field.

5. Review the clinical behavior of Hürthle cell tumors and evaluate a proposed classification scheme for these tumors that includes the ret/PTC oncogene.

ATA Guidelines for Surgical Management of Differentiated Cancer
Stephanie Lee, MD, PhD, Professor of Medicine, Boston University School of Medicine, and Associate Chief, Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, MA

Epidemiology: incidence of thyroid cancer rising in United States; Surveillance, Epidemiology, and End Results (SEER) national database shows increase mostly small (0.1-2.0 cm) nodules; however, not true for all states; eg, Massachusetts Cancer Directory shows increase in all thyroid cancers ≤5 cm

Staging: complicated; <45 yr of age—stage I (all tumors except thyroid cancers with distant metastases); >45 yr of age—stage II (tumors 2-4 cm); stage III (tumors >2 cm, except when level VI nodes involved or microscopic invasion present [20%-30% of patients])

Risk factors not in TNM system: tumor subtype—tall cell, columnar cell, insular, trabecular, and diffuse sclerosing all have aggressive presentation and increased risk for death; Hürthle cell and poorly differentiated tumors also have aggressive presentation; vascular invasion and multicentricity—not part of guidelines; lymph node metastases— guidelines simply state “presence of level VI nodes” or “presence of lateral neck nodes”; need to know whether nodes microscopic or clinically relevant; capsular invasion directly through node increases risk for persistent disease; inability to concentrate 131I—unknown until first 131 I treatment; additional factors—completeness of resection; male sex

Recurrence and death: initial stage predicts survival, but does not predict disease-free survival; initial age at diagnosis correlates with recurrence rate and death; young children have high recurrence rate (≤50%); as age at diagnosis increases, risk for recurrence decreases until 50 yr of age, then increases; risk for death low in younger age groups, possibly due to more normal ploidy in tumors; more genetic defects may be present in tumors of older patients; risk for distant metastases increases in older patients

Indeterminate lesions on fine needle aspiration (FNA): nodule >2.5 cm with normal thyrotropin (TSH) unlikely to be hot nodule; diagnostic ultrasonography (US) recommended before biopsy; after FNA, 10% to 12% risk for carcinoma in nodule; of these, ≈15% indeterminate, ie, unknown whether benign or malignant; radionuclide scanning recommended; American Thyroid Association (ATA) recommendation 9A—nodule must be autonomously functioning, ie, suppressed function in surrounding normal tissue; if no autonomy (cold nodule), consider lobectomy or total thyroidectomy; surgery indicated for nonautonomous nodule with indeterminate biopsy

Unilateral surgery: risk relatively low (≈20%); lower complication rate; can miss follicular variants of papillary thyroid carcinoma (PTC) and multifocal disease

Bilateral surgery: err toward bilateral surgery if surgeon highly skilled and complication rates low; clinical criteria—1) on US, if nodule shows intranodular vascularity, microcalcifications, or blurred margins, total thyroidectomy indicated; 2) nodule >4 cm has increased risk for malignancy and complications; 3) extremely atypical nodule; 4) older patient, especially older man; 5) history of irradiation (due to increased risk for development of benign and malignant nodules); 6) family history of thyroid cancer (5%-10% of patients have familial PTC); 7) positron emission tomography (PET) positivity; 8) molecular markers (correct combination of markers not yet determined); 9) nodules in contralateral lobe, even if small (because of need for continual monitoring)

ATA recommendation 10: if FNA “suspicious for” PTC (as opposed to “consistent with” PTC), surgery recommended, but extent of surgery depends on clinical suspicion; in speaker’s experience, ≈95% of patients with FNA suspicious for PTC have PTC and require total thyroidectomy

ATA guidelines for surgery of differentiated thyroid carcinoma: preoperative evaluation—data show preoperative US changed surgical procedure in only 15% to 20% of patients; generally, level VI lymph nodes cannot be seen; in patients with positive lateral lymph nodes (levels II, III, and IV), disease-free survival less; however, not important to perform prophylactic lateral neck dissections, since decrease in disease-free survival not statistically significant; ATA guidelines recommend preoperative US; speaker always does node survey; cytology and thyroglobulin aspirates also required; routine preoperative imaging with computed tomography (CT), magnetic resonance imaging (MRI), and PET not recommended; optimal surgery for PTC—bilateral surgery always recommended because 25% to 40% of patients have microscopic multifocal contralateral disease; reduces risk for recurrence, even in low-risk patients; facilitates long-term surveillance for recurrence; unilateral surgery—speaker performs if risk for clinical recurrence on opposite side very low and if worried about complications; data show improved survival with near-total, compared to less-than-total thyroidectomy for stage II and greater (not for stage I); increased risk for recurrence with unilateral surgery, even in low-risk patients (14% local recurrence vs 2% with bilateral; 19% in regional lymph nodes vs 6% with bilateral)

ATA recommendation 26: near-total or total thyroidectomy recommended for most patients with cancers >1 cm, but lobectomy may be sufficient for patients with tumors <1 cm, low risk, no history of irradiation, isolated disease, and no cervical nodes

Adenopathy and differentiated thyroid carcinoma: clinical cervical adenopathy ≈20%; microscopic adenopathy based on cytology probably 80% to 90%; adenopathy not always palpable or visible; level VI dissection may improve survival; currently recommended for all patients with PTC >1 cm; since now recognized that microscopic disease in level VI lymph nodes not large risk for mortality, new guidelines may recommend therapeutic level VI dissection if nodes palpable, seen at time of surgery, seen on US or other imaging, and lateral lymph node dissection for similar clinical indications; prophylactic central neck dissection indicated if patient has T3 or T4 disease, or evidence of invasion of surrounding tissues; extent of dissection will be better defined in new guidelines

Fine Needle Aspiration and Cancer Risk Assessment
Erik K. Alexander, MD, Assistant Professor of Medicine, Harvard Medical School, Division of Endocrinology, Diabetes, and Hypertension, and Associate Physician, Brigham and Women’s Hospital, Boston, MA

Nodule risk: overall risk for cancer 8% to 15% in any nodule >1 cm; clinical factors that modify risk include male sex, young age, and high-risk symptoms; if ≥1 of these present, risk increased 1.5- to 2-fold; current studies suggest that nodule size alone not predictive

Evaluation and diagnosis: assessment of serum TSH recommended for any nodule >1 cm; suppressed TSH indicates autonomous or toxic nodule; if TSH elevated, FNA recommended, preferably with US guidance; advantages of FNA—minimally invasive means of obtaining tissue for cytopathologic analysis; office-based; nonoperative; requires only local anesthesia; uses simple equipment, eg, 10 mL syringe, 25-gauge needle, cytology preparation material, US (optional)

FNA from 1990 onward: positive aspects—widespread adoption; improvement in FNA technique and cytologic analysis; increasing use of US; partial reduction in unnecessary surgery; negative aspects—increased nodule detection due to new imaging techniques; lack of consensus on procedure, leading to high variability, eg, US or palpation, needle size, number of passes, specimen preparation, handling of cystic nodules; inability to identify subgroup with benign nodules

National Cancer Institute thyroid FNA conference: resulted in emerging consensus on 1) which nodules to biopsy; 2) how to effectively perform FNA; 3) which results might be expected

Which nodules to biopsy: only those >1 cm; Ohio State data—indicate that tumor size clearly predicts recurrence and cancer death; support definition of stage-I disease as <1.5 cm (lower recurrence rate; high survival rate); 3 retrospective analyses show—2% to 3% of patients with small primary lesions have distant metastatic disease; almost all these cases involve cancers 9 to 10 mm in diameter; no data suggest distant metastases from 3- or 4-mm PTC; Machens et al (2005)—650 patients with well-differentiated thyroid carcinomas; performed Kaplan-Meier analyses of risk for aggressive tumor behaviors, eg, extrathyroidal growth; found that behavior changes at ≈1 cm; caveat—each patient unique and must be analyzed individually

Multinodularity: 40% to 50% of patients evaluated have ≥2 nodules >1 cm; not protective from malignancy; risk for cancer independent of number of nodules; data suggest >1 nodule should undergo FNA; subset analysis showed that cancer present in largest nodule ≈75% of time; >50% of patients had single cancer, even with ≥4 nodules >1 cm

How to perform FNA: subcutaneous lidocaine anesthesia—recommended; does not change specimen or results; administer at depth of 3 to 4 mm into subcutaneous tissue and over 3 to 7 sec to avoid bruising and pain; analgesia present in 40 to 60 sec; needle size—emerging consensus that 25- or 27-gauge needle produces excellent specimens and little bruising; typical thyroid follicle fits into inner diameter of 25-gauge needle; aspiration time—most follicular cells obtained in first 2 to 3 sec; thereafter, trauma and bruising occur, making specimen difficult to interpret; number of needle passes—consensus that 3 needle passes effective and sufficient

Cancer risk assessment from FNA: roughly two-thirds of cytology reports show no evidence of malignant cells (highly accurate and predictive finding, since with US guidance, false-negative rate <1%); 5% positive for PTC; remaining 20% to 25% indeterminate (surgery recommended); ≈50% of patients with abnormal cytology found to have benign disease at surgery

Speaker’s approach: anyone with nodule or suspected nodule should have US; look for nodules >1 cm; assess clinical symptoms if present; finding of purely cystic process on US conclusively benign; partially cystic findings not necessarily benign; assessment of and discussion with individual patient paramount; must balance malignant risk with patient’s comorbidities, longevity, and tolerance for risk; then make decision about FNA

Hürthle Cell Tumors: Using Molecular Methods to Define a New Classification
Jeremy L. Freeman, MD, Professor of Otolaryngology, Temmy Latner/Dynacare Chair in Head and Neck Oncology, University of Toronto, Faculty of Medicine, and Otolaryngologist-in-Chief, Mount Sinai Hospital, Toronto, ON

Definitions: Hürthle cell—phenotypically, follicular cell with hyperchromatic cytoplasm; polyhedral; rich in mitochondria; can occur in almost any thyroid condition, ie, not specific; Hürthle cell tumor (HCT)—50% to 75% Hürthle cells; ≈6% of all thyroid tumors; usually divided into adenomas (benign) and carcinomas (malignant), based on criteria for classification of follicular tumors, ie, vascular and/or capsular invasion; PTCs with ≥75% Hürthle cells classified as Hürthle cell PTCs, based on papillary architecture; however, diagnostic nuclear features often obscured by nuclear hyperchromasia

Clinical behavior of HCTs: controversial; some aggressive, some indolent; many metastasize; if truly follicular cell derivatives, they should not metastasize; if they are unique type of tumor in their own class, perhaps metastasis one of characteristics; speaker’s study—looked at 45 tumors; found clinical behavior as described in literature for well-differentiated thyroid cancers (eg, disease-specific survival, disease-free survival); vascular invasion altered prognosis for disease-free and tumor-specific survival; vascular invasion and stage influenced outcome; no treatment factors correlated with outcome

Genetics: ret/PTC oncogene injected into HCTs in transgenic mice resulted in PTC; transfection of ret/PTC oncogene into cultured primary human thyroid cells resulted in nuclear alterations consistent with cytologic features of PTC; no correlation of ret/PTC with structural features of aggressive behavior; ret/PTC positive in some HCTs; ret/PTC not specific (incidence in PTC, 5%-80%), but when ret/PTC expression present, almost certain to be thyroid cancer

Speaker’s study: hypothesis—Hürthle cell PTC behaves like other PTC, with lymphatic spread and indolent clinical course, not similar to follicular carcinoma; methods—56 patients; tumors removed by 4 surgeons and analyzed by one surgical pathologist

Classification: Hürthle cell adenoma—no capsular or vascular invasion; no ret/PTC gene rearrangement found on immunohistochemistry or reverse transcriptase polymerase chain reaction (PCR); truly benign; Hürthle cell carcinoma—vascular or capsular invasion but no ret/PTC gene rearrangement; Hürthle cell PTC—any Hürthle cell tumor with ret/PTC rearrangement

Hürthle cell PTC: many had papillary architecture with 75% Hürthle cells; some had heavy lymphocytic infiltrates; some showed classic follicular architecture with nuclear features of PTC; some had solid architecture (no follicle formation) but hyperchromatic nuclei; some had follicular architecture with strong immunoreactivity for ret/PTC; some had solid architecture with variable immunoreactivity for ret/PTC

Outcomes: most patients had adenomas; 5 of 20 patients with Hürthle cell carcinomas developed metastases (one developed lymph node metastases); none of benign tumors developed metastases

Interpretation: division of malignant HCT into follicular and papillary variants may account for heterogeneity in clinical behavior that has caused controversy; one would expect Hürthle cell PCT to behave in keeping with other PTCs, with preponderance for lymphatic spread and more indolent clinical course; Hürthle cell carcinoma might account for reports of more aggressive Hürthle cell cancers, since these are really follicular cancers; definite trend for lymph node metastases in ret/PTC-positive patients; molecular biologic model augments and complements histopathologic diagnosis